NCT02757768: PLUS

A Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Men With OAB Symptoms While Taking Tamsulosin Hydrochloride for Lower Urinary Tract Symptoms (LUTS) Due to Benign Prostatic Hyperplasia (BPH)

Completed Phase 4 Results posted Last updated 12 November 2024

What this trial tests

Phase 4 trial testing Mirabegron in Benign Prostatic Hyperplasia in 715 participants. Completed in 11 September 2018.

Timeline

13 June 2016

Primary endpoint
14 August 2018

11 September 2018

Quick facts

Lead sponsor	Astellas Pharma Global Development, Inc.
Phase	Phase 4
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	715
Start date	13 June 2016
Primary completion	14 August 2018
Estimated completion	11 September 2018
Sites	79 locations across France, Italy, United Kingdom, Germany, Poland, Canada, United States, Spain

Drugs / interventions tested

• Mirabegron (MIRABEGRON) — full drug profile →
• Placebo
• Tamsulosin Hydrochloride — full drug profile →

Conditions studied

• Benign Prostatic Hyperplasia — all drugs for Benign Prostatic Hyperplasia →
• Overactive Bladder — all drugs for Overactive Bladder →

Sponsor

Astellas Pharma Global Development, Inc. — full company profile →

Who can join

40 and older, male only, with Benign Prostatic Hyperplasia or Overactive Bladder. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline to End of Treatment (EoT) in Mean Number of Micturitions Per Day Primary · Baseline and Week 12

Participants recorded micturitions in the e-diary during three days. The mean number of micturitions was calculated as the average number of times a participant recorded a micturition per day during the 3-day period. Only voluntary micturitions were counted and the episodes of incontinence were not included.

Group	Value	95% CI
Mirabegron	-2.00	± 0.13
Placebo	-1.62	± 0.15

Change From Baseline to Week 4, Week 8, and Week 12 in Mean Number of Micturitions Per Day Secondary · Baseline and Weeks 4, 8, and 12

Participants recorded micturitions in the e-diary during three days. The mean number of micturitions was calculated as the average number of times a participant recorded a micturition per day during the 3-day period. Only voluntary micturitions were counted and the episodes of incontinence were not included.

Week 4

Group	Value	95% CI
Mirabegron	-1.42	± 0.13
Placebo	-1.32	± 0.13

Week 8

Group	Value	95% CI
Mirabegron	-1.89	± 0.13
Placebo	-1.38	± 0.13

Week 12

Group	Value	95% CI
Mirabegron	-1.95	± 0.13
Placebo	-1.56	± 0.13

Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Volume Voided Per Micturition Secondary · Baseline and Weeks 4, 8, and 12

The mean volume voided per micturition during 3 days of the 3-day micturition diary period.

Week 4

Group	Value	95% CI
Mirabegron	17.74	± 1.98
Placebo	13.87	± 1.98

Week 8

Group	Value	95% CI
Mirabegron	22.56	± 2.31
Placebo	16.28	± 2.32

Week 12

Group	Value	95% CI
Mirabegron	26.31	± 2.53
Placebo	17.32	± 2.52

EoT

Group	Value	95% CI
Mirabegron	25.57	± 2.42
Placebo	16.32	± 2.42

Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Incontinence Episodes Per Day Secondary · Baseline and Weeks 4, 8, and 12

An incontinence episode was defined as the complaint of any involuntary leakage of urine. The mean number of incontinence episodes per 24 hours was calculated as the average number of times a participant recorded an incontinence episode per day during the 3-day micturition diary period.

Week 4

Group	Value	95% CI
Mirabegron	-0.97	± 0.18
Placebo	-0.84	± 0.18

Week 8

Group	Value	95% CI
Mirabegron	-1.29	± 0.22
Placebo	-1.20	± 0.23

Week 12

Group	Value	95% CI
Mirabegron	-1.48	± 0.22
Placebo	-1.23	± 0.23

EoT

Group	Value	95% CI
Mirabegron	-1.45	± 0.21
Placebo	-1.15	± 0.22

Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Urgency Episodes (Grade 3 or 4) Per Day Secondary · Baseline and Weeks 4, 8, and 12

Urgency was defined as a complaint of a sudden, compelling desire to pass urine, which is difficult to defer. An urgency episode was defined as any micturition or incontinence episode with a severity of grade 3 or 4, assessed by participants based on the Patient Perception of Intensity of Urgency Scale (PPIUS), where 0 = No urgency; 1 = Mild urgency; 2 = Moderate urgency, could delay voiding a short while; 3 = Severe urgency, could not delay voiding; 4 = Urge incontinence, leaked before arriving to the toilet. The mean number of urgency episodes (grade 3 and/or 4) per day was calculated as the

Week 4

Group	Value	95% CI
Mirabegron	-1.79	± 0.15
Placebo	-1.53	± 0.15

Week 8

Group	Value	95% CI
Mirabegron	-2.68	± 0.17
Placebo	-1.97	± 0.17

Week 12

Group	Value	95% CI
Mirabegron	-2.86	± 0.17
Placebo	-2.21	± 0.17

EoT

Group	Value	95% CI
Mirabegron	-2.90	± 0.17
Placebo	-2.24	± 0.17

Change From Baseline to Week 4, Week 8, Week 12 and EoT in International Prostate Symptom Score (IPSS) Total Score Secondary · Baseline and Weeks 4, 8, and 12

The International Prostate Symptom Score (IPSS) consists of 7 questions concerning urinary symptoms and 1 question concerning quality of life (QoL) with total score and subscores (voiding, storage and QoL). The IPSS total score classification ranges from mild (0 to 7) to moderate (8 to 19) or severe (20 to 35). Higher IPSS scored indicated more severe symptoms.

Week 4

Group	Value	95% CI
Mirabegron	-3.9	± 0.3
Placebo	-4.0	± 0.3

Week 8

Group	Value	95% CI
Mirabegron	-5.0	± 0.3
Placebo	-5.2	± 0.3

Week 12

Group	Value	95% CI
Mirabegron	-5.9	± 0.3
Placebo	-5.5	± 0.3

EoT

Group	Value	95% CI
Mirabegron	-5.7	± 0.3
Placebo	-5.6	± 0.3

Change From Baseline to Week 4, Week 8, Week 12 and EoT in IPSS Subscale Voiding Score Secondary · Baseline and Weeks 4, 8, and 12

The International Prostate Symptom Score (IPSS) consists of 7 questions concerning urinary symptoms and 1 question concerning quality of life (QoL) with total score and subscores (voiding, storage and QoL). Each question is assigned points from 0 to 5 indicating increasing severity of the particular symptom. The subscale voiding score is the sum of the responses to 4 voiding symptoms questions (incomplete emptying, intermittency, weak stream, and straining). The lowest and highest possible scores range from 0 to 20 (mildly symptomatic to severely symptomatic). A higher score is indicative of w

Week 4

Group	Value	95% CI
Mirabegron	-1.7	± 0.2
Placebo	-2.1	± 0.2

Week 8

Group	Value	95% CI
Mirabegron	-2.2	± 0.2
Placebo	-2.5	± 0.2

Week 12

Group	Value	95% CI
Mirabegron	-2.5	± 0.2
Placebo	-2.5	± 0.2

EoT

Group	Value	95% CI
Mirabegron	-2.5	± 0.2
Placebo	-2.6	± 0.2

Change From Baseline to Week 4, Week 8, Week 12, and EoT in IPSS Subscale Storage Score Secondary · Baseline and Weeks 4, 8, and 12

The International Prostate Symptom Score (IPSS) consists of 7 questions concerning urinary symptoms and 1 question concerning quality of life (QoL) with total score and subscores (voiding, storage and QoL). Each question is assigned points from 0 to 5 indicating increasing severity of the particular symptom. The subscale storage score is the sum of the responses to 3 storage symptoms questions (frequency, urgency, and nocturia). The lowest and highest possible scores range from 0 to 15 (mildly symptomatic to severely symptomatic). A higher score is indicative of worse condition and a negative

Week 4

Group	Value	95% CI
Mirabegron	-2.2	± 0.1
Placebo	-1.9	± 0.1

Week 8

Group	Value	95% CI
Mirabegron	-2.8	± 0.2
Placebo	-2.6	± 0.1

Week 12

Group	Value	95% CI
Mirabegron	-3.3	± 0.2
Placebo	-3.0	± 0.2

EoT

Group	Value	95% CI
Mirabegron	-3.3	± 0.2
Placebo	-3.0	± 0.2

Change From Baseline to Week 4, Week 8, Week 12 and EoT in IPSS Subscale Quality of Life (QoL) Score Secondary · Baseline and Weeks 4, 8, and 12

The International Prostate Symptom Score (IPSS) consists of 7 questions concerning urinary symptoms and 1 question concerning quality of life (QoL) with total score and subscores (voiding, storage and QoL). The QoL assessment was a single question asking the participant how he would feel about tolerating his current level of symptoms for the rest of his life. The lowest and highest possible score ranges from 0 to 6 (very pleased to terrible). A higher score is indicative of worse condition and a negative change from baseline indicates an improvement.

Week 4

Group	Value	95% CI
Mirabegron	-0.9	± 0.1
Placebo	-0.7	± 0.1

Week 8

Group	Value	95% CI
Mirabegron	-1.3	± 0.1
Placebo	-1.1	± 0.1

Week 12

Group	Value	95% CI
Mirabegron	-1.5	± 0.1
Placebo	-1.3	± 0.1

EoT

Group	Value	95% CI
Mirabegron	-1.4	± 0.1
Placebo	-1.3	± 0.1

Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Urgency Incontinence Episodes Per Day Secondary · Baseline and Weeks 4, 8 and 12

Urgency Incontinence was defined as the complaint of involuntary leakage accompanied by or immediately proceeded by urgency. The mean number of urgency incontinence episodes was calculated as the average number of times a participant recorded an urgency incontinence episode per day during the 3-day micturition diary period.

Week 4

Group	Value	95% CI
Mirabegron	-0.97	± 0.18
Placebo	-0.85	± 0.18

Week 8

Group	Value	95% CI
Mirabegron	-1.29	± 0.22
Placebo	-1.19	± 0.23

Week 12

Group	Value	95% CI
Mirabegron	-1.52	± 0.22
Placebo	-1.24	± 0.22

EoT

Group	Value	95% CI
Mirabegron	-1.49	± 0.21
Placebo	-1.16	± 0.21

Change From Baseline to Week 4, Week 8, Week 12 and EoT in Symptom Bother Score Secondary · Baseline and Weeks 4, 8, and 12

Overactive bladder symptoms were assessed using the Symptom Bother Scale of the Overactive Bladder questionnaire (OAB-q). The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQoL). The symptom bother portion consists of 8 questions, rated on a 6-point Likert scale (1 through 6). The total symptom bother score was calculated from the 8 answers and then transformed to range from 0 (least severity) to 100 (worst severity). Lower scores on OAB-q symptom bother indicate a better response.

Week 4

Group	Value	95% CI
Mirabegron	-13.73	± 0.91
Placebo	-11.98	± 0.92

Week 8

Group	Value	95% CI
Mirabegron	-18.72	± 1.00
Placebo	-14.88	± 0.99

Week 12

Group	Value	95% CI
Mirabegron	-20.93	± 1.07
Placebo	-18.03	± 1.06

EoT

Group	Value	95% CI
Mirabegron	-20.18	± 1.04
Placebo	-18.07	± 1.05

Change From Baseline to Week 4, Week 8, Week 12 and EoT in Total Health Related Quality of Life (HRQL) Score Secondary · Baseline and Weeks 4, 8, and 12

The OAB-q is a self-reported questionnaire with 33 questions relating to symptom bother and health-related quality of life (HRQoL). The HRQoL portion consists of 25 HRQoL items comprising 4 HRQoL subscales (Coping, Concern, Sleep, and Social Interaction), each item was scored 1-6. The total score was calculated by adding the 4 HRQoL subscale scores and transforming to a scale from 0 to 100, with higher scores indicating better quality of life. A higher score on OAB-q HRQL indicated a better response.

Week 4

Group	Value	95% CI
Mirabegron	9.08	± 0.80
Placebo	10.43	± 0.80

Week 8

Group	Value	95% CI
Mirabegron	13.06	± 0.85
Placebo	13.53	± 0.85

Week 12

Group	Value	95% CI
Mirabegron	15.90	± 0.91
Placebo	15.00	± 0.90

EoT

Group	Value	95% CI
Mirabegron	15.07	± 0.89
Placebo	15.12	± 0.89

Adverse events — posted to ClinicalTrials.gov

Time frame: From first double-blind medication intake until 30 days after last double-blind medication intake; 16 weeks. Reporting threshold: 2%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Mirabegron

Serious: 10/352 (3%)

Deaths: 0/352

Placebo

Serious: 8/354 (2%)

Deaths: 0/354

Serious adverse events (22 terms)

Reaction	System	Mirabegron	Placebo
Acute myocardial infarction	Cardiac disorders	—	—
Angina pectoris	Cardiac disorders	—	—
Angina unstable	Cardiac disorders	—	—
Chronotropic incompetence	Cardiac disorders	—	—
Intestinal obstruction	Gastrointestinal disorders	—	—
Peripheral swelling	General disorders	—	—
Neuroborreliosis	Infections and infestations	—	—
Urosepsis	Infections and infestations	—	—
Ankylosing spondylitis	Musculoskeletal and connective tissue disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—
Osteoarthritis	Musculoskeletal and connective tissue disorders	—	—
Glioblastoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Pancreatic carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—
Cerebral infarction	Nervous system disorders	—	—
Lacunar stroke	Nervous system disorders	—	—
Sciatica	Nervous system disorders	—	—
Renal colic	Renal and urinary disorders	—	—
Urinary retention	Renal and urinary disorders	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—
Knee arthroplasty	Surgical and medical procedures	—	—
Peripheral arterial occlusive disease	Vascular disorders	—	—

Other adverse events (2 terms — click to expand)

Reaction	System	Mirabegron	Placebo
Hypertension	Vascular disorders	—	—
Headache	Nervous system disorders	—	—

Most-reported serious reactions: Acute myocardial infarction, Angina pectoris, Angina unstable, Chronotropic incompetence, Intestinal obstruction, Peripheral swelling, Neuroborreliosis, Urosepsis.

Data from ClinicalTrials.gov NCT02757768 adverse events section.

Sponsor's own description

The purpose of the study was to assess the efficacy, safety, and tolerability of mirabegron versus placebo in men with overactive bladder (OAB) symptoms while taking tamsulosin hydrochloride for lower urinary tract symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH).

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. Efficacy and safety of daily mirabegron 50 mg in male patients with overactive bladder: a critical analysis of five phase III studies.
   Tubaro A, Batista JE, Nitti VW, Herschorn S, et al · · 2017 · cited 40× · PMID 28588652 · DOI 10.1177/1756287217702797
2. Message from our President
   Zorn K, Bhojani N, Elterman D, Goldenberg S, et al · · 2020